Although kinase oncogenes are well-characterized drivers of cancer development, much less is known regarding the role of phosphatases in transformation. The serine-threonine protein phosphatase 2A (PP2A) is implicated in the regulation of numerous signaling pathways and may function as a tumor suppressor. PP2A is a heterotrimeric protein complex, and several isoforms exist for each of the three subunits, creating a diverse family of related enzymes that regulate specific physiological functions. The diversity of PP2A heterotrimers has complicated previous efforts to establish the cellular function of specific PP2A subunits. I propose to take a three-tiered approach toward a systematic characterization of PP2A complexes in cancer progression. Using loss of function experiments I plan to assess the contribution of particular PP2A complexes in human cell transformation. By using genome scale approaches, I will determine alterations of particular PP2A regulatory subunits in human cancers. I will then focus on deciphering the molecular roles of specific PP2A complexes in tumor suppression through a directed proteomics approach together with cell transformation assays. [unreadable] [unreadable] Public Health Relevance: These studies represent primary steps toward the identification of new targets that may have diagnostic and therapeutic potential in the treatment of cancer. [unreadable] [unreadable] [unreadable] [unreadable]